Benzoheterocyclicalkyl derivatives of 4-(2-keto-1-benzimidazolinyl)-piperidine

ABSTRACT

BENZOHETEROCYCLICALKYL DERIVATIVES OF 4-(2-KETO-1-BENZIMIDAZOLINYL)-PIPERIDINE, IN WHICH THE BENZOHETEROCYCLIC MOIETY IS THIANAPHTHENYL OR BENZOFURANYL, OPTIONALLY SUBSTITUTED BY CHLORO, BROMO, FLUORO, METHYL, METHOXY OR TRIFLUOROMETHYL, HAVE NEUROLEPTIC ACTIVITY. THE COMPOUNDS ARE GENERALLY PREPARED FROM EITHER THE BENZOHETEROYCLICALKYL HALIDE BY REACTION WITH THE APPROPRIATE AMINE OR THE BENZOLHETEROCYCLIC AMINE BY CONDENSATION WITH A 5,5-BIS(B-HALOETHYL)BARBITURIC ACID.

Unitcd States Patent 3,712,898 BENZOHETEROCYCLICALKYL DERIVATIVES OF4-(2-KETO-l-BENZIMIDAZOLINYL)-PIPERIDINE Carl Kaiser, Haddon Heights,N.J., and Charles L. Zirkle,

Berwyn, Pa., assignors to Smith Kline & French Laboratories,Philadelphia, Pa.

N0 Drawing. Original application Oct. 28, 1968, Ser. No. 771,320, nowPatent No. 3,629,267, dated Dec. 21, 1971. Divided and this applicationMar. 10, 1971, Ser. No. 123,090

Int. Cl. C07d 99/04, 99/06 US. Cl. 260-29357 Claims ABSTRACT OF THEDISCLOSURE Benzoheterocyclicalkyl derivatives of4-(2-keto-l-benzimidazolinyl)-piperidine, in which the benzoheterocyclicmoiety is thianaphthenyl or benzofuranyl, optionally substituted bychloro, bromo, fluoro, methyl, methoxy or triiiuoromethyl, haveneuroleptic activity. The compounds are generally prepared from eitherthe benzoheteroyclicalkyl halide by reaction with the appropriate amineor the benzoheterocyclic amine by condensation with a 5,5-bis-(B-haloethyDbarbituric acid.

This application is a division of application Ser. No. 771,320 filed onOct. 28, 1968, now US. Pat. No. 3,629,- 267 issued Dec. 21, 1971.

This invention relates to novel benzoheterocyclicalkyl derivatives of4-(2-keto-l-benzimidazolinyl)-piperidine, 4-(2-keto-l-benzimidazolinyl)-l,2,3,-6-tetrahydropyridine, 1-phenyl-1,3,8-triazaspiro[4,S]decan-4-one and2,4,9-triazaspiro[5,5]undecan-l,3,5-trione. These compounds have usefulpharmacodynamic activity and more specifically have neuroleptic activityas demonstrated in standard animal pharmacological test procedures.Exemplary of the activity of the compounds of this invention is themoderate to marked decreased motor activity, catalepsy, hypotonia andptosis produced in rats upon oral administration of doses ranging from1.0 to 50.0 rug/kg. At these doses no toxicity is observed.

The compounds of this invention are represented by the following generalstructural formula:

R (CH2) r-Z FORMULA I in which:

R represents hydrogen, chloro, bromo, fluoro, methyl,

methoxy or trifiuoromethyl; Y represents oxygen or sulfur; n representsa positive whole integer from 2 to 4; and Z represents 3,712,898Patented Jan. 23, 1973 Preferred compounds include those of Formula Iwherein R is in the 5 or 6-position, Y is sulfur, n is 3 and thebenzoheterocyclic moiety is 3-substituted.

The compounds of this invention may be used in the form of apharmaceutically acceptable acid addition salt having the utility of thefree base. Such salts, prepared by methods well known to the art, areformed with both inorganic or organic acids, for example: maleic,fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic,methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric,salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic,citraconic, aspartic, stearic, palmitic, itaconic, glycolic,p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric and nitric acids.

The compounds of this invention wherein Z is 4-(2-keto-l-benzimidazolinyl) 1 piperidyl, 4-(2-keto lbenzimidazolinyl)1,2,3,6 tetrahydro l pyridyl or l-phenyl-l,3,8-triazaspiro[4,5]dec 8 yl4 one are generally prepared from a benzoheterocyclicalkyl halide havingthe formula:

FORMULA II wherein R Y and n are as defined for Formula I and X ishalogen, preferably chlorine or bromine, by reaction with theappropriate amine (HZ). The halides of Formula II are prepared fromcorresponding alkanoic acids (n is 1 to 3) via reduction with lithiumaluminum hydride to the alcohol followed by reaction with a phosphorustrihalide, such as phosphorus tribromide, to give the alkyl halide. Therequired alkanoic acids are obtained as described in Belgian Pat. No.711,675.

The compounds of Formula I wherein Z is 2,4,9-triazaspiro[5,5]undec-9-yl1,3,5 dione are generally prepared from a benzoheterocyclicalkyl aminehaving the formula:

FORMULA III wherein R,, Y and n are as defined in Formula I by reactionwith a 5,5-dis(;9-haloethyl)-barbiturie acid derivative, the halo groupbeing iodo or bromo. The amines of Formula III are prepared fromcorresponding alkanoic acids (n is 1 to 3) via reacting: the acid withthionyl chloride to give the acid chloride which is treated with ammoniaand reducing the resulting amide with aluminum hydride to yield thealkyl amine.

The compounds of this invention may be administered orally orparenterally in conventional dosage unit forms such as tablets,capsules, injectables or the like, by incorporating the appropriate doseof a compound of Formula I, either as the free base or an acid additionsalt thereof, with carriers according to accepted pharmaceuticalpractices.

The foregoing is a general description of how to prepare the compoundsof this invention. The following examples illustrate the preparation ofspecific compounds having neuroleptic activity. However this should notbe construed as limiting the scope of the invention since appropriatevariations in the starting materials will produce other products setforth hereinabove.

PREPARATIONS (A) 3-(3-thianapht-henyl)-propy 1 bromide (Formula II) To amixture of 4.0 g. (0.105 In.) of lithium aluminum hydride in 1000 ml. ofdry ether is added a solution of 10.7 g. (0.052 m.) of3-(3-thianaphthenyl)-propionic acid in 50 ml. of dry tetrahydrofuran,dropwise with stirring. The resulting mixture is stirred and refluxedfor four hours, decomposed and filtered. The dried filtrate isevaporated in vacuo and the residue distilled to give 3-(3-thianaphthenyl)-propanol, B.P. 133-158" C./0.5 mm.

A solution of 9.2 g. (0.0479 m.) of 3-(3-thianaphthenyl)-propanol in 250ml. of dry ether is stirred while ml. of phosphorus tribromide in 50 m1.of dry ether is added dropwise. The resulting mixture is stirred andrefluxed for one hour, poured into ice-water and the layers separated.The ether layer is washed, dried and evaporated in vacuo to give an oilwhich is distilled to give 3-(3-thianaphthenyl)-propyl bromide, B.P.147190 C./ 0.1 mm.

(B) 3-(3-thianaphthenyl)-propyl amine (Formula III) A mixture of 5.2 g.(0.025 m.) of 3-(3-thianaphthenyl)- propionic acid and 15 ml. (0.025 m.)of thionyl chloride is allowed to stand at room temperature overnight,diluted with benzene and evaporated in vacuo to give the acid chloride.The latter is dissolved in ether and treated with an excess of aqueousammonia. The resulting mixture is refluxed for one hour and theseparated organic layer is washed, dried and concentrated to give3-(3-thianaphthenyl)-propionamide. The amide is reduced with anequimolar amount of lithium aluminum hydride in dry ether to yield3-(3-thianaphthenyl)-propylamine.

Following the procedures of part A or B above, other R -substitutedthianaphtheneor benzofuranalkanoic acids are similarly converted tocorresponding alkyl bromides or amines.

EXAMPLE 1 A mixture of 4.7 g. (0.0219 111.) of 4-(2 keto 1-benzimidazolinyl) 1,2,3,6 tetrahydropyridine, 8.0 g. (0.0314 m.) of 3-(3thianaphthenyl)-propyl bromide, 1.84 g. (0.0219 m.) of sodiumbicarbonate and 0.3 g. of potassium iodide in 500 ml. of dry toluene isstirred and refluxed for four days. The reaction mixture is evaporatedin vacuo and the residue is dissolved in chloroform/water. The waterlayer is washed with chloroform and the total chloroform solution iswashed with dilute hydrochloric acid, dried and evaporated in vacuo togive 1-[3-(3 thianaphthenyl) propyl] 4 (2 keto 1- benzimidazolinyl)1,2,3,6 tetrahydropyridine; hydrochloride, M.P. 252254 C.

Similarly, by employing 3-(5-chloro-2-thianaphthenyl)- propyl bromide(obtained from the propionic acid) in the above reaction there isproduced 1-[3-(5-chloro-2- thianaphthenyl)-propyl] 4 (2 keto 1benzimidazolinyl)-1,2,3,6-tetrahydropyridine.

EXAMPLE 2 A mixture of 8.0 g. (0.0314 in.) of3-(3-thianaphtheny-l)-propyl bromide, 4.4 g. (0.0203 m.) of4-(2-ketol-benzimidazolinyl)-piperidine, 1.71 g. (0.0203 m.) of sodiumbicarbonate and 0.3 g. of potassium iodide in 500 ml. of dry toluene isstirred and refluxed for four days. The reaction mixture is evaporatedin vacuo and the residue dissolved in chloroform/water. The layers areseparated and further worked up as in Example 1 to yieldl-[3-(3-thianaphthenyl)-propyl] 4(2-keto-1-benzimidazolinyl)-piperidine; hydrochloride, M.P. 287294 C.

Similarly, by employing an equivalent amount of 3-(5-methyl-3-thianaphthenyl)-propyl bromide (obtained from the propionicacid) as described above there is prepared 1-[3-(5-methyl 3thianaphthenyl) propyl] 4 (2- ketol-benzimidazolinyl) -piperidine.

EXAMPLE 3 Following the procedures of Example 1, a mixture of 5.0 g.(0.0216 in.) of l-phenyl-1,3,8-triazaspiro[4,5]decan- 4-one, 8.0 g.(0.0314 m.) of 3-(3-thianaphthenyl)-propyl bromide, 1.82 g. (0.0216 In.)of sodium bicarbonate and 0.3 g of potassium iodide in 500 ml. of drytoluene is stirred and refluxed for four days, then filtered while hot.The filtrate is evaporated in vacuo and the residue Worked up to give1-phenyl-8-[3(3-thianaphthenyl)-propyl]-1,3,8-triazaspiro[4,5]decan-4-one; hydrochloride, M.P. 258- 260 C.

Use of 3-(6-methoxy-2-thianaphthenyl)-propyl bromide (obtained from thepropionic acid) as the reactant above yields 1phenyl-8-[3-(6-methoxy-Z-thianaphthenyl)-pr0- pyl]-1,3,8-triazaspiro[4,5] decan-4-one.

EXAMPLE 4 A solution of 6.0 g. (0.03 m.) of 3-(3-thianaphthenyl)-propylamine in 60 ml. of anhydrous ethanol is added to a suspension of11.7 g. (0.027 m.) of 5,5-bis(fi-iodoethyl) barbituric acid in m1. ofanhydrous ethanol and the mixture is shaken two and one-half hours inthe dark under nitrogen. One equivalent of dry silver oxide and, aftershaking for three days, one more equivalent of silver oxide is added.The mixture is then shaken for three hours, briefly heated to 60 C.,filtered and evaporated. The residue is purified by chromatography togive 9-[3-(3-thianaphthenyl)-propyl]-2,4,9-triazaspiro[5,5]undecan 1,3,5-trione.

Similarly, by reacting 3-(3-benzoturanyl)-propylamine (obtained from thepropionic acid) with 5,5-bis(;3-iodoethyl)barbituric acid as describedabove there is prepared 9 [3-(3-benzofuranyl)-propyl]-2,4,9-triazaspiro-[5,5 1 undecan-1,3,5-trione.

EXAMPLE 5 Following the procedure of Example 1, an equivalent amount of3-(2-benzofuranyl)-propyl bromide (obtained from the propionic acid) isreacted with 4-(2-keto-1- benzimidazolinyl)-1,2,3,6-tetrahydropyridinein the presence of sodium bicarbonate and potassium iodide to yield uponworkup 1-[3-(2-benzofuranyl)-propyl]-4-(2-keto-1-benzimidazolinyl)-1,2,3,6-tetrahydropyridine.

By employing instead 3-(3-benzofuranyl)-propyl bromide as the reactantabove there is obtained 1-[3-(3- benzofuranyl)-propyl]4-(2-keto 1benzimidazolinyD- 1,2,3,6-tetrahydropyridine.

EXAMPLE 6 Following the procedure of Example 1, 3(6-fluoro-3-thianaphthenyl)-propyl bromide (obtained from the propionic acid) isreacted with 4-(2-keto-1-benzimidazolinyl)- 1,2,3,6-tetrahydropyridineto give 1-[3-(6-fluoro-3-thianaphthenyl)-propyl]4-(2-kcto-1-benzimidazolinyl) 1,2,3, 6-tetrahydropyridine.

Use of 3-(6-trifluoromethyl-3-thianaphthenyl) propyl bromide asdescribed above yields 1-[3-(6-trifluoromethyl-3-thianaphthenyl)-propyl]4 (2 keto-l-benzimidazolinyl)-1,2,3,6-tetrahydropyridine.

EXAMPLE 7 Following the procedure of Example 1, 3-(6-bromo-3-benz0furanyl)-propyl bromide (obtained from the pro pionic acid) isreacted with 4-(2-keto-l-benzimidazolinyl)- 1,2,3,6-tetrahydropyridineto yield the product 1-[3-(6- bromo-3-benzofuranyl)-propyl]-4-(2-keto 1benzimidazolinyl) 1,2,3,6-tetrahydropyridine.

EXAMPLE 8 Following the procedures of Examples 1 and 3, a mixture of2-(3-thianaphthenyl)-ethyl bromide (obtained from the acetic acid) andl-phenyl-l,3,8-triazaspiro[4,5] decan-4-one is stirred and refluxed forfour days in the presence of sodium bicarbonate and potassium iodide toyield upon workup the product, 1-phenyl-8-[2-(3-thianaphthenyl)-ethyl]-1,3, S-triazaspiro [4,5 decan-4-one.

Similarly, employing 4-(6meth0xy-3-benzofuranyl)- butyl bromide(obtained from the butyric acid) as described above results in theformation of 1-pheny1-8-[4- (6-methoxy-3-benzofuranyl) butyl] 1,3,8triazaspiro- [4,51decan-4-one.

What is claimed is:

1. A chemical compound of the formula:

or a pharmaceutically acceptable acid addition salt thereof wherein:

R is hydrogen, chloro, bromo, fluoro, methyl, methoxy ortrifluoromethyl; Y is oxygen or sulfur; n is a Whole integer from 2 to4; and Z is References Cited UNITED STATES PATENTS 3,070,606 12/1962Anderson 260330.5

3,558,637 1/1971 Kaiser et al 260293.4

HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner US. Cl.X.R. 260-29358, 295 M

